1. Field of the Invention
The present invention is in the fields of medicine, pharmaceuticals, nutraceuticals, endocrinology and cardiology. The invention provides compositions comprising a statin, an inhibitor of the angiotensin converting enzyme, an antiplatelet compound and an anti-hyperglycemic compound for use in the treatment and/or prevention of cardiometabolic risk factors of Metabolic Syndrome and treatment and/or prevention of Metabolic Syndrome.
2. Related Art
Cardiovascular Disease
Metabolic Syndrome, previously known as Syndrome X, is an intermediate state between normal metabolism and type 2 diabetes mellitus. It is an emerging epidemic which has been defined as a constellation of metabolic risk factors predisposing people to coronary heart disease and chronic kidney disease. The constellation includes abdominal obesity, atherogenic dyslipidemia, hypertension, and proinflammatory and prothombotic states, with or without glucose intolerance. Each of these characteristics is a significant risk factor for development of vascular dysfunction and cardiovascular disease. Important organ systems involved in Metabolic Syndrome include the vasculature, heart, adipose tissue, liver and skeletal muscle.
Although the underlying mechanisms for Metabolic Syndrome have not been entirely elucidated, resistance to the cellular action of insulin is known to be a cardinal feature, as evidenced by the presence of both hyperinsulinemia and insulin resistance in obesity, hypertension, type 2 diabetes mellitus and dyslipidemia.
Abdominal obesity or visceral obesity specifically refers to the accumulation of adipose tissue in the abdominal viscera, and this condition may be visualized through a number of imaging techniques. The anthropometric indices such as the waist circumference, indirectly reflect the abdominal fat, even though they do not discriminate between the subcutaneous or visceral location. The presence of relatively high amounts of adipose tissue generally correspond to a relatively high risk of metabolic changes such as insulin resistance, dyslipidemia and high blood pressure, representing a high risk of diabetes mellitus and cardiovascular disease.
Hypertension is one of the cardinal components of Metabolic Syndrome. Hypertension itself is a major and independent cardiovascular risk factor. Patients with hypertension are more likely to be insulin resistant and in these patients hypertension tends to cluster with other metabolic risk factors.
Dyslipidemia in patients with Metabolic Syndrome is more complex than a simple quantitative derangement of certain lipoprotein particles. Normally, this condition consists of high levels of triglycerides (Tg) and apoliprotein B (ApoB), small low density lipoprotein cholesterol (LDL-C) particles and low High density lipoprotein cholesterol (HDL-C), that eventually compromise the integrity of the arterial wall. LDL-C is the primary target of therapy in Metabolic Syndrome.
Insulin resistance is characterized as a state in which a typical amount of insulin produced by the pancreas, and resident in the blood stream, fails to interact normally with cells, making it more difficult for glucose to pass from the blood stream into muscle cells, liver cells and adipose tissue cells. Individuals with insulin resistance sometimes have elevated fasting glucose or glucose intolerance. Hyperinsulinemia and insulin resistance are both implicated in the pathogenesis of hypertension, obesity, type 2 diabetes, and atherosclerosis.
Not all risk factors need to be present in an individual to be diagnosed as having Metabolic Syndrome. Normally, Metabolic Syndrome is diagnosed when an individual presents three or more of the following criteria:                a) Abdominal obesity: waist circumference>102 cm in men and >88 cm in woman        b) Hypertriglyceridemia: ≧150 mg/dL,        c) Low HDL cholesterol: <40 mg/dL in men and <50 mg/dL in women,        d) High blood pressure: ≧130/85 mmH, or        e) High fasting glucose: ≧110 mg/dL.        
In addition, prothrombotic and proinflammatory states are related to Metabolic Syndrome. Patients with Metabolic Syndrome often have elevated prothrombotic biomarkers, such as fibrinogen and plasminogen activator inhibitor-1. Likewise, cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and acute phase reactants, such as C-reactive protein are also elevated. However, currently no definitions have included pro-inflammatory state as component of Metabolic Syndrome.
Treatment of Metabolic Syndrome
The major approaches to manage individuals with Metabolic Syndrome are to reduce the underlying causes and to treat hypertension and other cardiometabolic risk factors and to reduce insulin resistance. Treatment of Metabolic Syndrome includes life style changes along with pharmacologic therapy.
Weight reduction is the first line of intervention in obese individuals with Metabolic Syndrome. Obesity guidelines put emphasis on weight reduction, using behavioral changes to reduce caloric intake and increase physical activity. The first aim of weight loss is to achieve a reduction of about 7% to 10% from baseline total body weight during a period of 6 to 12 months. This requires a caloric intake reduction of 500 to 1000 calories per day. Weight reduction has a synergistic effect on LDL lowering and decreases all of the risk factors of Metabolic Syndrome.
Beyond weight control and reduction of total calories, diet should be low in saturated fats, trans fats, cholesterol, sodium and simple sugars. In addition, there should be an increase in intake of fruits, vegetables and whole grains.
Beyond reducing underlying causes, attention must be given to the metabolic risk factors, such as atherogenic dyslipidemia, hypertension and elevated fasting glucose among others.
Atherogenic dyslipidemia: LDL cholesterol is the primary target of lipid-lowering therapy among individual with Metabolic Syndrome. Statins are a series of substances that inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) and thus reduce LDL cholesterol. Ezetimibe and bile acid sequestrants are other LDL-lowering agents.
The secondary target of lipid-lowering therapy is non-HDL cholesterol (elevated ApoB) in patients with high triglyceride levels. A tertiary aim in patients with atherogenic dyslipidemia is to raise HDL-C when it is reduced. There are two drug therapy options to achieve secondary and tertiary goals. The first option is to intensify statin therapy, and the second option is to add nicotinic acid or fibrate. However, when fibrate is used in combination with statin, caution should be heeded as there is a high risk for severe myopathy, specially when higher doses of statin are used.
Elevated fasting glucose: In Metabolic Syndrome diagnosis, elevated fasting glucose includes both Impaired Fasting Glucose (IFG) and impaired glucose tolerance (IGT). The American Diabetes Association recommends that metformin should be considered as a drug therapy for individuals with impaired fasting glucose and/or impaired glucose tolerance.
Hypertension: Mild elevation of blood pressure often can be effectively controlled with lifestyle therapies—weight control, increased physical activity, sodium reduction, and increased consumption of fresh fruits and vegetables and low-fat dairy products. If hypertension cannot be adequately controlled by lifestyle therapies, antihypertensive drugs are necessary to prevent long-term adverse effects. Angiotensin converting enzymes (ACE) inhibitors are the first line therapy for hypertension in Metabolic Syndrome.
Prothrombotic and proinflammatory state: There is currently no specific therapy directly acting on prothrombotic or proinflammatory state. Low-dose aspirin may be considered for patients with coronary heart disease, diabetes, or high-risk profile of developing Metabolic Syndrome. C-reactive protein may be used to monitor proinflammatory state in individuals. A high C-reactive protein concentration greater than 3 mg/dL in blood may be used as cut-off indicating higher risk inflammation associated with Metabolic Syndrome. Medications such as statins, nicotinic acid, fibrates, ACE inhibitors, and thiazolidinediones, can also decrease C-reactive protein concentration.
Metabolic Syndrome is a constellation of endogenous risk factors that increase the risk of development both cardiovascular disease or type 2 diabetes mellitus, therefore there is no specific treatment exclusively for the syndrome. Those people suffering from Metabolic Syndrome generally are treated with a number of different agents, in particular hypoglycemic agents, blood pressure medication, as well as cholesterol lowering drugs. Very often, drug combinations will be necessary to manage multiple risk factors. Several drug combinations have been proposed; such drug combinations are disclosed in the following review of patents, most of them related to the treatment and prevention of the cardiovascular disease resulting from Metabolic Syndrome.
McGovern et al., in U.S. Pat. No. 5,140,012, disclose the use of pravastatin alone or in combination with an angiotensin converting enzyme (ACE) inhibitor, to prevent onset of restenosis following angioplasty. The disclosure is limited to a single inhibitor of HMGCoA, pravastatin and does not includes an antiplatelet agent such as acetylsalicylic.
Liang et al. in U.S. Pat. No. 6,576,256 discloses a combination of a cholesterol lowering agent, a renin angiotensin system inhibitor and the antiplatelet agent aspirin. This invention does not include a hypoglycemic agent.
U.S. Pat. Nos. 5,461,039 and 5,593,971 disclose the use of a cholesterol-lowering drug, alone or in combination with ACE inhibitors, to reduce hypertension in normotensive individuals who have insulin resistance. The disclosed methods are limited to use in normotensive individuals who are insulin-resistant.
Bortolini et al., in U.S. Appl. Pub. No. 2007/0275996, disclose the use of a pharmaceutical composition consisting of a statin for the prevention or treatment of Metabolic Syndrome. A composition consisting of only a lipid lowering agent is not adequate for the treatment of Metabolic Syndrome since Metabolic Syndrome consists of multiple components requiring an specific treatment for each one of these co-morbidities.
Olokatun et al., in U.S. Pat. No. 5,622,985, disclose that HMGCoA inhibitors, particularly pravastatin, when used alone or alternatively in combination with an angiotensin converting enzyme (ACE) inhibitor, decrease the risk of a second heart attack in a patient who has a substantially normal cholesterol level.
Cornett et al., in U.S. Appl. Pub. No. 2006/0154959, claim the use of a formulation comprising a cicletanine (a diuretic drug, usually used in the treatment of hypertension) and a second agent for the treatment of at least one of diabetes, Metabolic Syndrome, dyslipidemia, or complications related to any of these diseases. This patent does not specify which second agent is most suitable, and is restricted to the use of only one agent in addition to cicletanine compositions.
Mexican patent number MX218975 entitled “Composición Farmacéutica que Contiene Estatina y Aspirina” discloses the use of a statin in combination with acetylsalicylic acid to reduce hypercholesterolemia and the risk of myocardial infarction.
Alvarez-Ochoa et al., in Mexican request patent number PA/A/2005/014063, disclose the use of a pharmaceutical composition comprising an antihypertensive and cholesterol lowering compound. The selected hypolipidemic agent and antihypertensive agent were simvastatin and amlodipine, respectively. The disclosure is limited to the use of amlodipine as the antihypertensive agent.
As discussed above, these combinations do not include a hypoglycemic agent, or include hypoglycemic agents which are not suitable for treatment of Metabolic Syndrome (e.g. sulfonylureas or glitazones, which have been shown to promote weight gain). Biguanide metformin is the most suitable hypoglycemic agent to be used in a polypill intended for the treatment and prevention of Metabolic Syndrome since, in addition to its antihyperglycemic effect, it has shown an important effect on reducing the lipid profile, reducing inflammatory state and promoting weight loss.
Only one application (U.S. Appl. Pub. No. 2007/0015839) disclosed the use of metformin in combination with other drugs as an effective method for treating diabetes and Metabolic Syndrome. However, this application comprises a formulation containing two doses of hypoglycemic agent (metformin) to be taken at two different times and a pill containing metformin, simvastatin and a renin-angiotensin system inhibitor. The disadvantage of this application is related to compliance, since individuals who have to take different pills, are less like to do so. Additionally, the use of an antiplatelet agent is optional. In contrast, the lipid lowering agent referred to in the present invention is more powerful and with more pleiotropic effects than simvastatin contained in U.S. Appl. Pub. No. 2007/0015839, giving as a result a most safe and efficacious scheme treatment. The major approaches to manage individuals with Metabolic Syndrome are to reduce most of the underlying causes and to treat hypertension and other cardiometabolic risk factors including hyperglycemia and dyslipidemia individually. Therefore, individuals with Metabolic Syndrome may be required to take five or six different pills, directed at a specific disease, either at once or at different times during the day. Compliance is a critical problem for proper treatment of Metabolic Syndrome. Thus, combining drugs at a lower dose in a single dosage will greatly improve compliance, efficacy and security of the treatment.